Doxorubicin cardiac dysfunction: Effects on calcium regulatory proteins, sarcoplasmic reticulum, and triiodothyronine

Utilizing a model of chronic doxorubicin cardiomyopathy, this study examines the relationship between changes in expression and function of calcium handling proteins and contractile dysfunction. A possible mechanism to account for this relationship is suggested. New Zealand white rabbits were injected with either doxorubicin (1 mg/kg, twice weekly for 8 wk) or 0.9% NaCl. Gene transcript, protein levels, and the function of several proteins from the left ventricle were assessed. Protein levels of sarcoplasmic reticulum (SR) Ca ²⁺ transporting ATPase (SERCA2a and b), Ca²⁺ release channel (RYR2), calsequestrin, Na/Ca exchanger, mRNA levels of RYR2, and [ ³H]-ryanodine binding (B_max) to RYR2 were significantly decreased in doxorubicin-treated rabbits; protein levels of phospholamban, dihydropyridine receptor α2 subunit, and SR Ca²⁺ loading rates were not decreased. However, only protein levels of SERCA2 and RYR2, mRNA levels of RYR2, and B_max of RYR2 significantly regressed with left-ventricular fractional shortening. Analysis of contractile function of atrial preparations isolated from doxorubicin-treated rabbits revealed that doxorubicin diminished contractility (dF/dt) of rest-potentiated contractions consistent with SR dysfunction. Serum concentrations of free triiodothyronine (T3) decreased in doxorubicin-treated rabbits. Our results suggest that chronic doxorubicin administration in the rabbit causes a SR-dependent contractile dysfunction that may result, in part, from decreased T3.